A systematic review of the drug-drug interaction between Statins and Quinolones

Background Statins are widely used in cardiovascular disease (CVD) as a common lipid-lowering drug, while quinolones are widely used for the treatment of infectious diseases. It is common to see CVD in combination with infectious diseases, therefore it is often the case that statins and quinolones are used in combination. Data suggest combinations of statin and quinolone may be associated with potentially life-threatening myopathy, rhabdomyolysis and acute hepatitis. This systematic review aims to characterize data regarding patients affected by the statin-quinolone interaction. Methods The purpose of this systematic review was to collect and evaluate the evidence surrounding statin-quinolone drug interactions and to discuss related risk mitigation strategies. The following databases were searched: PubMed (Medline), Embase, Scopus, and Cochrane Library. The systematic electronic literature search was conducted with the following search terms. In this study, three types of search terms were used: statins-related terms, quinolones-related terms, and drug interactions-related terms. Results There were 16 case reports that met the criteria for qualitative analysis. Patients were involved in the following adverse reactions: rhabdomyolysis (n = 12), acute hepatitis (n = 1), muscle weakness (n = 1), hip tendinopathy (n = 1), or myopathy (n = 1). In the included literature, patients vary in the dose and type of statins they take, including simvastatin (n = 10) at a dose range of 20–80 mg/d and atorvastatin (n = 4) at a dose of 80 mg/d. There were 2 patients with unspecified statin doses, separately using simvastatin and atorvastatin. The quinolones in combination were ciprofloxacin (n = 9) at a dose range of 800–1500 mg/d, levofloxacin (n = 6) at a dose range of 250–1000 mg/d, and norfloxacin (n = 1) in an unspecified dose range. 81% of the case patients were over 60 years of age, and about 1/3 had kidney-related diseases such as diabetic nephropathy, post-transplantation, and severe glomerulonephritis. Nearly two-third of the patients were on concomitant cytochrome P450 3A4 (CYP3A4) inhibitors, P-glycoprotein (P-gp) inhibitors, or organic anion transporting polypeptide 1B1 (OATP1B1) inhibitors. Conclusion Patients treated with statin-quinolone combination should be monitored more closely for changes in aspartate aminotransferase or creatine kinase (CK) levels, and muscle symptoms, especially in patients with ciprofloxacin or levofloxacin, with simvastatin and high-dose atorvastatin, over 60 years of age, with kidney-related diseases, and on concomitant CYP3A4 inhibitors. Supplementary Information The online version contains supplementary material available at 10.1186/s40360-024-00760-8.


Background
Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, represent widely prescribed drugs currently available for the reduction of low-density lipoprotein cholesterol, which are widely used as the mainstay therapy for the management of dyslipidaemia, including primary and secondary prevention of cardio-and cerebro-vascular disease [1].It is estimated that around 200 million people worldwide are taking statins, which makes up 3% of the global population [2].Although considered efficacious and safe, statins are associated with adverse effects, such as skeletal muscle toxicity and hepatic adverse reactions [3].Globally, between 5.9 and 7.0% (depending on the diagnostic criteria used) of statin-treated patients experience symptoms of intolerance [4,5].Risk factors for statinassociated adverse drug reaction include advanced age (especially > 80 years, more common in women), thinness, frailty, multisystem disease (e.g., chronic renal insufficiency, especially due to diabetes), combination of multiple medications, perioperative period, combination of special medications and diet, and excessive statin doses.Certain medications increase the risk, including colchicine, verapamil, diltiazem, fibrates, protease inhibitors, and azoles [6].So among all risk factors, drug-drug interactions play an important role and deserve further study.
Quinolones are widely used for the treatment of infectious diseases (e.g., respiratory tract infections, urinary tract infections, bacterial prostatitis, skin and other soft tissue infections, bone and joint infections, gastrointestinal infections) [7].Adverse reactions of quinolones have certain commonalities, most commonly tendon and joint pain, and some degree of hepatotoxicity [8].It is common to see CVD in combination with infectious diseases, therefore it is often the case that statins and quinolones are used in combination.Data suggest statin and quinolone combination may be associated with potentially life-threatening myopathy, rhabdomyolysis and acute hepatitis.
This systematic review aims to characterize data regarding patients affected by the statin-quinolone interaction, as well as describe potential etiologies, clinical ramifications, and risk-mitigation strategies associated with the drug-drug interaction between statins and quinolones.

Data sources and searches
We conducted a literature search following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for systematic reviews.A literature search of the following databases was performed: PubMed (Medline), Embase, Scopus, and Cochrane library.We searched for all synonyms including "statins", "quinolones" and "drug interactions", and every statin and quinolone drug name.Search terms used across all databases included all synonyms for "statins", "quinolones" and "drug interactions", and every statin and quinolone drug name (for the complete search strategy, see Attachment 1), but filters varied depending on the database utilized.All databases were searched for literature up to the end of October 2022.Only articles reporting on original data, including non randomized, randomized studies, observational cohort studies, case series or case reports in adult patients aged 18 years and older were eligible for inclusion.
This study was reviewed and approved by the Medical Ethics Committee of the First People's Hospital of Linping District, (approval number: Linping First People's Hospital Ethics 2022 Paper No. 49).

Data charting and evidences synthesis
In order to map the evidence, the PRISMA template was adapted.We collected data from two authors (JF and LX), then we resolved chart conflicts from a third author (HM).From each study, extract the following information: author (year), study design, patient demographics and comorbidities, statin regimen, statin intensity, quinolones regimen, quinolones dose, quinlones indication, concomitant CYP3A4 inhibitors, concomitant P-gp inhibitors, concomitant OATP1B1 inhibitors, time from quinolones initiation to onset of adverse drug reaction(ADR), hospitalization or not, ADR developed, tests for diagnostic purposes, laboratory examination, presentation, treatment and regression of ADR, time to improvement of symptoms, time to normalization of laboratory indicators, outcomes of patients, and mortality after adverse drug event.

Results
The search retrieved 478 records, of which 387 were screened by investigators.The specific reasons for exclusion were as follows: (1) duplicate records (n = 91); (2) Irrelevant when found by the investigator reading the abstract (n = 347); (3) Reports which were excluded by full-text search (N = 24): no concurrent statin-quinolones therapy (n = 9); no statin-quinolones interactions (n = 11); incomplete outcome reports (n = 3); duplicate articles (n = 1).Figure 1 depicts the PRISMA flow diagram for the screening, and ultimately, there were 16 case reports that met the criteria for qualitative analysis (Table 1).

Discussion
In this systematic review, 16 patients experienced ADRs related to the combination of statins and quinolones.These reported ADRs included rhabdomyolysis (n = 12), acute hepatitis (n = 1), muscle weakness (n = 1), hip tendinopathy (n = 1) or myopathy (n = 1), with the vast majority (81%) of these symptoms being associated with CK elevation.The drug combinations presenting with ADRs were, in order of frequency, simvastatin and ciprofloxacin (n = 6), simvastatin and levofloxacin (n = 4), atorvastatin and ciprofloxacin (n = 3), atorvastatin and levofloxacin (n = 2), and simvastatin and norfloxacin (n = 1).In summarising the most common characteristics of patients affected by statin-quinolone interactions described in this systematic review, 10 subjects (62.5% of all patients) were combined with other drugs such as CYP3A4 inhibitor, P-gp inhibitor, OATP1B1 inhibitor, 13 subjects (81.25% of all patients) were over 60 years of age; 14 (88% of all studies) reported patients taking medium to high intensity statins and 5 subjects (31.25% of all patients) identified patients with comorbid renal disease.On average, ADRs occurred after 15 days of combined statin and quinolone therapy.All patients were hospitalised for the aforementioned adverse reactions, 13 patients chose to discontinue the drug, seven of them discontinuing both statin and quinolone, 4 patients discontinuing only the statin and two discontinuing only the quinolone; 7 patients used hydration, 2 patients underwent dialysis; and 1 patient adjusted the type of statin.In addition, genetic analysis was performed in only one of the 16 cases to clarify possible factors for the development of ADR.All patients improved after appropriate treatment.
Through this systematic review, we found the types of the statins and quinolones were risk factors for ADR following the combination of statins and quinolones.Statins can be grouped according to differences in enzymatic metabolism, for example simvastatin and atorvastatin are mainly metabolised by CYP3A4 isoenzymes, whereas fluvastatin and pravastatin are mainly metabolised by CYP2C9 enzymes [25].In the included reports, the types of statins were dominated by simvastatin (n = 11) and atorvastatin (n = 5), and the types of quinolones were ciprofloxacin (n = 9), levofloxacin (n = 6) and norfloxacin (n = 1), which are all CYP3A4 inhibitors.Therefore, combination of statins and quinolones metabolised by CYP3A4 are at greater risk of drug interactions.Secondly, the dose of the statin was also a risk factor for ADR following the combination of statins and quinolones.In this systematic review, statin doses were mentioned in 14 of the 16 cases, all at moderate to high intensity statins.Atorvastatin had an ADR risk only at the highest dose (80 mg/d), whereas simvastatin had a risk at all doses (dose range fluctuated from 20 to 80 mg/d).However, the dose and treatment duration of quinolones may not affect the ADRs that occur after the combination of statin and quinolone.Quinolone doses were mentioned in 13 of the 16 cases, with seven cases reporting ciprofloxacin doses between 400 and 750 mg twice daily and six cases reporting levofloxacin doses between 250 and 1000 mg/ day.Only 4 of the 16 cases used levofloxacin at a dose slightly above the usual dose.Quinolone treatment duration were mentioned in 9 of 16 case reports, with specific durations ranging from 4 days to 3 months.Thirdly, the combined medications were risk factors for ADR following the combination of statins and quinolones.In 16 publications, 10 patients were combined with CYP3A4 inhibitors, P-gp inhibitors, and OATP1B1 inhibitors that affect statin metabolism, such as amiodarone, amlodipine, cyclosporine, clarithromycin and ticagrelor.Amiodarone is an inhibitor of the pharmacological enzyme P450 3A4 and P-gp, which affects simvastatin and atorvastatin, with the most adverse reactions reported in combination with simvastatin.Amlodipine is known to have a competitive inhibitory effect on the metabolic activity of CYP3A4/5.Pharmacokinetic modelling has shown that 10 mg amlodipine significantly increases the bioavailability and decreases the clearance of simvastatin  when it is combined with simvastatin [26,27].In addition, combination therapy with cyclosporine A and simvastatin increased the area under the curve of simvastatin by eightfold by competing for the drug binding site of the cytochrome P450 3A4 enzyme [28][29][30].Also cyclosporine A is a potent inhibitor of P-glycoprotein and prolongs levofloxacin concentrations in tissues.Clarithromycin is an inhibitor of organic anion transporter polypeptide 1B1 (OATP1B1), a transporter involved in the metabolic pathway of all statins, including those not metabolised by CYP3A4 [31].Ticagrelor is metabolised by cytochrome P4503A4, which, like most statins, competitively inhibits CYP3A4 isoenzymes, leading to the accumulation of statins metabolised by CYP3A4.Finally, patients with creatinine clearance below 30 ml/min and older patients were all reported increasing risks of statinrelated myopathy [26][27][28][29][30].In this systematic review, we also found that elderly patients and renal insufficiency are all factors that contribute to the increased risk of combining statins and quinolones.We found 13 patients (81.25% of all patients) were over 60 years of age and 5 patients (31.25% of all patients) were with combined renal insufficiency.
In general, the first step after an ADR is to stop the suspected drug.According to the relevant guidelines, the main treatment principle for rhabdomyolysis is to promote the excretion of myoglobin from the kidneys and protect renal function, which is divided into the following four options: (1) hydration: saline infusion is recommended; (2) alkalinize the urine: apply sodium bicarbonate to alkalize the urine; (3) correction of electrolyte disturbances caused by rhabdomyolysis, such as low blood calcium and high blood potassium; (4) dialysis at the appropriate time [32,33].Faced with ADRs from the combination of statins and quinolones, 13 patients discontinued their medication, of whom 7 discontinued both statins and quinolones, 4 discontinued only statins, 2 discontinued only quinolones and 1 adjusted the type of statin; 7 patients chose to rehydrate and 2 went on dialysis; all patients subsequently showed improvement.We found a significant effect regardless of whether statins or quinolones were discontinued.Regarding the choice of hydration medication, some chose 0.9% sodium chloride injection, some chose intravenous crystalloid, some chose intravenous crystalloid hypotonic solution, and 2 patients combined catheterisation or the diuretic furosemide as an adjunct to diuresis.In the early stages of ADR, fluid replacement, diuresis and active correction of electrolyte disturbances are the mainstays, and sodium bicarbonate can be used to alkalinise the urine.If severe kidney damage has been caused or if symptoms of oliguria or anuria develop, haemodialysis or haemofiltration treatment can be administered.In most cases, doctors were able to detect ADRs caused by the combination of statins and quinolones and treated them as recommended, and the prognosis was generally good.

Conclusions
In this systematic review, 16 cases reported ADRs while receiving a statin-quinolone combination.The pharmacokinetic and pharmacodynamic properties of quinolones and statins, the combination of CYP3A4 isoenzymes and P-gp inhibitors and OATP1B1 inhibitors, reduced renal function and advanced age are all factors that contribute to adverse reactions following the combination of quinolones and statins.Therefore, patients treated with statinquinolone combinations should be monitored intensively for changes in liver function and muscle enzymes and if ADRs develops, it can be reversed by timely drug discontinuation, hydration, diuresis and dialysis.

Fig. 1
Fig. 1 PRISMA flow diagram for Statin-Quinolones drug-drug interaction database searching of records

Table 2
Presentation, treatment and recovery of ADRs in case reports of statin-quinolone interactions

developed Tests for diagnos- tic purposes Laboratory examination Presentation of ADR Treatment of ADR Regression of ADR
Creatine Kinase, MB Form; Scr: Serum creatinine Both the time to improvement of symptoms and the time to normalization of laboratory indicators were calculated from the time the measures were taken Improved NoNote CK: Creatine Kinase; LD: Lactate dehydrogenase; AST: Aspartate transaminase; ALT: Alanine amiotransferase; MB: Myoglobin; Tn: Troponin; CK-MB: